ZAP70

zeta chain of T cell receptor associated protein kinase 70, the group of Syk family tyrosine kinases|SH2 domain containing

Basic information

Region (hg38): 2:97713576-97744327

Previous symbols: [ "SRK" ]

Links

ENSG00000115085 ∙ NCBI:7535 ∙ OMIM:176947 ∙ HGNC:12858 ∙ Uniprot:P43403 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• combined immunodeficiency due to ZAP70 deficiency (Supportive), mode of inheritance: AR
• combined immunodeficiency due to ZAP70 deficiency (Strong), mode of inheritance: AR
• combined immunodeficiency due to ZAP70 deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoimmune disease, multisystem, infantile-onset 2; Immunodeficiency 48	AR	Allergy/Immunology/Infectious	In Autoimmune disease, multisystem, infantile-onset 2, individuals may demonstrate multiple autoimmune sequelae that may be refractory to immunosuppressants, and HSCT has been described as effective; In Selective T-cell defect, prophylactic measures, in the short term, include IVIG administration as well as antiinfectious prophylaxis; If blood products are necessary, they should be irradiated and CMV and EBV-negative; Live vaccines should be avoided, and immunizations should be deferred until reconstitution of the immune system; HSCT has been described as effective in some individuals	Allergy/Immunology/Infectious	2511270; 8124727; 8202713; 8202712; 10574909; 10748099; 11123350; 11412303; 11463783; 18509675; 19548248; 20301777; 23124046; 26783323

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ZAP70 gene.

• ZAP70-Related Severe Combined Immunodeficiency (10 variants)
• not provided (3 variants)
• Combined immunodeficiency due to ZAP70 deficiency (3 variants)
• Combined immunodeficiency (2 variants)
• Autoimmune disease, multisystem, infantile-onset, 2 (1 variants)
• ZAP70-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ZAP70 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	2	127	5	135
missense	2	2	151	4	1	160
nonsense	7	1	2			10
start loss			1			1
frameshift	4		1			5
inframe indel						0
splice donor/acceptor (+/-2bp)	1	1				2
splice region			15	13		28
non coding	1	2	12	56	21	92
Total	15	7	169	187	27

Highest pathogenic variant AF is 0.0000131

Variants in ZAP70

This is a list of pathogenic ClinVar variants found in the ZAP70 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-97713589-C-A		Combined immunodeficiency due to ZAP70 deficiency • not specified	Benign (Jan 24, 2024)
2-97713598-C-A		Combined immunodeficiency due to ZAP70 deficiency	Likely benign (Jan 13, 2018)
2-97713642-C-T		Combined immunodeficiency due to ZAP70 deficiency	Uncertain significance (Jan 12, 2018)
2-97713755-A-G		not specified	Benign (Jan 24, 2024)
2-97713815-TGTGTGCGG-T			Benign (Jul 15, 2021)
2-97713902-G-A		not specified	Likely benign (May 25, 2017)
2-97713925-T-A		Combined immunodeficiency due to ZAP70 deficiency	Benign (Jan 13, 2018)
2-97713935-T-G		Severe combined immunodeficiency disease	Uncertain significance (Jun 14, 2016)
2-97713957-T-C		Combined immunodeficiency due to ZAP70 deficiency	Benign (Jan 13, 2018)
2-97723901-A-C		not specified	Benign (Nov 12, 2023)
2-97724039-G-T			Uncertain significance (Sep 16, 2018)
2-97724043-G-C		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Nov 06, 2018)
2-97724052-G-A		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Aug 18, 2019)
2-97724053-C-T		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Apr 04, 2023)
2-97724057-C-G		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Dec 29, 2021)
2-97724061-C-G		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Nov 08, 2022)
2-97724073-G-C		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Nov 16, 2020)
2-97724073-G-T		Inborn genetic diseases	Uncertain significance (Apr 28, 2023)
2-97724082-T-C		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Jun 26, 2020)
2-97724084-G-A		ZAP70-Related Severe Combined Immunodeficiency	Likely benign (Oct 18, 2022)
2-97724084-G-C		ZAP70-Related Severe Combined Immunodeficiency	Likely benign (Oct 05, 2022)
2-97724086-G-T		ZAP70-Related Severe Combined Immunodeficiency	Uncertain significance (Dec 27, 2021)
2-97724116-C-A		ZAP70-Related Severe Combined Immunodeficiency • Combined immunodeficiency due to ZAP70 deficiency	Uncertain significance (Sep 02, 2021)
2-97724117-G-A		ZAP70-Related Severe Combined Immunodeficiency	Likely benign (Jan 13, 2023)
2-97724126-G-A		ZAP70-Related Severe Combined Immunodeficiency	Likely benign (Aug 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ZAP70	protein_coding	protein_coding	ENST00000264972	12	26303

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.877	0.123	125730	0	14	125744	0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.76	257	415	0.619	0.0000300	4010
Missense in Polyphen		97	190.4	0.50945		1794
Synonymous	1.09	168	187	0.899	0.0000156	1186
Loss of Function	4.11	5	28.8	0.173	0.00000141	329

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000120	0.000119
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000557	0.0000527
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000671	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). {ECO:0000269|PubMed:11353765, ECO:0000269|PubMed:12051764, ECO:0000269|PubMed:1423621, ECO:0000269|PubMed:20135127, ECO:0000269|PubMed:26903241, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8702662, ECO:0000269|PubMed:9489702}.
• Disease: DISEASE: Immunodeficiency 48 (IMD48) [MIM:269840]: A form of severe immunodeficiency characterized by a selective absence of CD8+ T-cells. {ECO:0000269|PubMed:11123350, ECO:0000269|PubMed:11412303, ECO:0000269|PubMed:18509675, ECO:0000269|PubMed:8124727, ECO:0000269|PubMed:8202713}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Autoimmune disease, multisystem, infantile-onset, 2 (ADMIO2) [MIM:617006]: An autosomal recessive, autoimmune disorder characterized by systemic manifestations including blistering skin disease, uncontrollable bullous pemphigoid, inflammatory colitis, autoimmune hypothyroidism, proteinuria and nephrotic syndrome. {ECO:0000269|PubMed:26783323}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Primary immunodeficiency - Homo sapiens (human);T cell receptor signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Natural killer cell mediated cytotoxicity - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Prolactin Signaling Pathway;T-Cell Receptor and Co-stimulatory Signaling;JAK-STAT;T-Cell antigen Receptor (TCR) pathway during Staphylococcus aureus infection;Ras Signaling;Inflammatory Response Pathway;Interferon type I signaling pathways;T-Cell antigen Receptor (TCR) Signaling Pathway;lck and fyn tyrosine kinases in initiation of tcr activation;role of mef2d in t-cell apoptosis;activation of csk by camp-dependent protein kinase inhibits signaling through the t cell receptor;t cell receptor signaling pathway;Prolactin;Generation of second messenger molecules;Translocation of ZAP-70 to Immunological synapse;TCR signaling;CD4 T cell receptor signaling-ERK cascade;TCR;Immune System;Adaptive Immune System;BCR;IL-7 signaling;JAK STAT pathway and regulation;EPO signaling;Class I PI3K signaling events;VEGF;TCR signaling in naïve CD8+ T cells;TCR signaling in naïve CD4+ T cells;CD4 T cell receptor signaling-JNK cascade;CD4 T cell receptor signaling-NFkB cascade;CD4 T cell receptor signaling (Consensus)

Recessive Scores

• pRec: 0.629

Intolerance Scores

• loftool: 0.0533
• rvis_EVS: -1.16
• rvis_percentile_EVS: 6.17

Haploinsufficiency Scores

• pHI: 0.393
• hipred: Y
• hipred_score: 0.793
• ghis: 0.574

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.858

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Zap70
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; cellular phenotype; immune system phenotype; skeleton phenotype; respiratory system phenotype; normal phenotype; hematopoietic system phenotype

Zebrafish Information Network

• Gene name: zap70
• Affected structure: pro-T cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: adaptive immune response;protein phosphorylation;immune response;peptidyl-tyrosine phosphorylation;T cell differentiation;intracellular signal transduction;T cell activation;B cell activation;beta selection;positive thymic T cell selection;negative thymic T cell selection;positive regulation of T cell differentiation;positive regulation of alpha-beta T cell differentiation;positive regulation of alpha-beta T cell proliferation;protein autophosphorylation;positive regulation of calcium-mediated signaling;T cell receptor signaling pathway;T cell aggregation;T cell migration
• Cellular component: immunological synapse;cytoplasm;cytosol;plasma membrane;cell-cell junction;T cell receptor complex;membrane raft
• Molecular function: phosphotyrosine residue binding;protein tyrosine kinase activity;non-membrane spanning protein tyrosine kinase activity;protein binding;ATP binding